Hexahydro imidazoquinolines

ABSTRACT

A series of novel substituted hexahydro imidazoquinoline compounds have been prepared from the corresponding 2aminomethyl-1,2,3,4-tetrahydroisoquinolines. These compounds are useful in the field of chemotherapy as anti-schistosomal agents. Preferred members include 2-(lower alkyl)-7-methyl-8-nitro1,2,3,3a,4,5-hexahydroimidazo-(1,5-a)-quinolines, 2-(lower alkyl)-7-hydroxymethyl-8-nitro-1,2,3,3a,4,5-hexahydroimidazo(1,5-a) -quinolines and 2-(lower alkyl)-7-methyl-8-chloro1,2,3,3a,4,5-hexahydroimidazo-(1,5-a)-quinolines, as well as various 1- and 9-substituted derivatives thereof.

United States Patent Baxter 14 1 June 6, 1972 [541 HEXAI-IYDROIMIDAZOQUINOLINES 3,557,120 1/1971 Archer ..260/288 [72] Inventor:Charles A. R. Baxter sandwich, England 3,565,902 2/1971 Wright ..260/268[73] Assignee: Pfirer Inc., New York, NY. FOREIGN PATENTS 0RAPPLICAT'ONS 22 Filed; 13, 1970 1,166,538 10/1969 Great Britain..260/288 [21 1 Appl' Primary Examiner-Donald G. Daus Attorney-Connollyand Hutz [30] Foreign Application Priority Data Feb. 19, 1969 GreatBritain ..8,882/69 [57] ABSIRACT A series of novel substituted hexahydroimidazoquinoline [52] U.S.Cl. ..260/283 S, 260/268 C, 260/283 CN,compounds have been prepared from the corresponding 2.

260/286 R, 260/288 R, 7 R, 42 /25aminomethyl-l,2,3,4-tetrahydroisoquinolines. These com- [5 Int. Clpoundsare useful in the of chemotherapy 35 anti- [58] Field of Search..260/288, 287, 283 S schiswsoma] agents P f d ber include 2-(loweralkyl )-7-methyl-8-nitrol ,2,3,3a,4,5-hexahydroimidazo-[ l ,5- [56]References Clted a]-quinolines, 2-(loweralkyl)-7-hydroxymethyl-8-nitrol,2,3,3a,4,5-hexahydroimidazo-[1,5-a]-quinolines and 2- UNlTED STATES PATENTS (loweralkyl)-7-methyl-8-chloro-1,2,3 ,3a,4,5-hex- 3,253,986 5/1966 Franklin..260/288 ahydroimidazo [1,5 a;-quin]ines, as we as various and 9-3,329,620 1968 Archer et substituted derivatives thereof. 3,454,5797/1969 Wright 3,393,195 7/1968 Thesing ..260/288 10 Claims, No DrawingsHEXAHYDRO MDAZOQUINOLINES BACKGROUND OF THE INVENTION This inventionrelates to certain new and useful hexahydro imidazoquinoline compoundsof principal interest to those in the field of chemotherapy. Moreparticularly, it is concerned with various novel substituted hexahydroimidazoquinolines and their non-toxic acid addition salts,-which are ofespecial value in view of their anti-schistosomal properties.

Inthe past, various attempts have been made by numerous investigators inthis particular field of therapy to obtain new and still better forms ofagents and/or methods for the treatment of schistosomiasis. In manyinstances, these efforts have further involved the synthesis and testingof various new organic compounds, particularly in the category ofnitrogen heterocycles. For instance, in British Pat. No. 837,306, thereis disclosed a series of dicarboxylic acid monopiperazides with a3-halogen-4-methylphenyl moiety located at the 1-position of thepiperazine ring that are reported as being active againstschistosomiasis. However, little is known about the effect of otherdi-nitrogen ring heterocycles in this area and the existing therapy,unfortunately, still suffers from a number of known drawbacks, such as,e.g., relatively low potency (requiring more than a single dose oftherapy), problems of toxicity, the lack of a demonstrated prophylacticeffect, etc.

SUMMARY OF THE INVENTION In accordance with the present invention, ithas now been surprisingly found that certain novel substituted hexahydroimidazoquinoline compounds are extremely useful when employed in thefield of drug therapy as anti-schistosomal agents. The novel compoundsof this invention are all selected from the group consisting ofsubstituted l,2,3,3a,4,5-hexahydroimidazo-[ l,5-a]-quinline bases of theformula:

and the N-oxide derivatives and pharmaceutically acceptable acidaddition salts thereof, wherein R, is a member selected from the groupconsisting of alkyl having from one to six carbon atoms, hydroxyalkylhaving from two to six carbon atoms, alkoxyalkyl having from two to sixcarbon atoms in the oxyalkyl moiety and from one to six carbon atoms inthe alkyl moiety, alkanoyloxyalkyl having from two to six carbon atomsin the oxyalkyl moiety and from two to six carbon atoms in the alkanoylmoiety, cycloalkyl having from three to six carbon atoms and phenylalkylhaving up to three carbon atoms in the alkyl moiety; R is a memberselected from the group consisting of methyl, formyl, hydroxymethyl,alkoxymethyl having from one to six carbon atoms in the alkyl moiety andalkanoyloxymethyl having from two to six carbon atoms in the alkanoylmoiety; R is a member selected from the group consisting of nitro,cyano, fluorine, chlorine and bromine; R and R are each a memberselected from the group consisting of hydrogen and alkyl having from oneto six carbon atoms, and R is a member selected from the groupconsisting of hydrogen, alkyl having from one to six carbon atoms,phenylalkyl having up to three carbon atoms in the alkyl moiety, phenyl,nitrophenyl, naphthyl, furyl, thienyl' and pyridyl. These compounds allpossess anti-schistosomal activity and are therefore, useful in thetreatment of schistosomiasis and/or for the control of schistosomeinfections.

Of especial interest in this connection are the preferred atoms (andmost preferably, a branched-chain alkyl having 3-4 carbon atoms, e.g.,isopropyl), R is methyl, hydroxymethyl, or ethoxymethyl, R is nitro orchloro, R, is hydrogen, R, is hydrogen or methyl, and R is hydrogen,methyl, ethyl, phenyl, nitrophenyl or thienyl. Typical member compoundsof the preferred class include such 2-(lower alkyl)-7-methyl (orhydroxymethyl)-8-nitro (or chloro)- 1,2,3,3a,4,5-hexahydroimidazo-[l,5-a]-quinolines as 2- isopropyl-7-methyl-8-nitrol ,2,3,3a,4,5-hexahydroimidazo-[ l ,S-al-quinoline, 1,7-dimethyl-2-isopropyl-8-nitrol ,2,3,3a,4,5-hexahydroimidazo-[l,5-a]-quinoline, 2- isopropyl7-hydroxymethyl-8-nitrol ,2,3,3a,4,5-hexahydroimidazo-[ l ,S-aI-quinoline, l-ethyl-2-isopropyl-7-methyl-S-nitrol ,2,3,3a,4,5hexahydroimidazo-[ l ,5-a]-quinoline,l-phenyl-2-isopropyl-7-methyl-8-nitro-l ,2 ,3 ,3 a,4,5hexahydroimidazo-[ l,5-a]-quinoline, 2-isopropyl-7,9- dimethyl-8-chlorol,2,3,3a,4,5-hexahydroimidazo-[ 1 ,5a]- quinoline,1,2,7-trimethyl-8-nitrol ,2,3,3a,4,5-hcxahydroimidazo-[ l,5-a]-quinoline, l-( 2-thienyl)-2-isopropyl- 7-methyl-8-nitrol,2,3,3a,4,5-hexahydroimidazo-[ l ,5-a]- quinoline,l-(2-nitrophenyl)-2-isopropyl-7-methyl-8-nitrol,2,3,3a,4,5-hexahydroimidazo-[l,5-a]-quinoline andlmethyl-2-isopropyl-7-ethoxymethyl-8-nitrol ,2 ,3,3a,4,5-hexahydroimidazo-[ l,5-a]quinoline, respectively. Theseparticular compounds are all highly potent as regards antischistosomalactivity.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the processemployed for preparing the novel compounds of this invention, anappropriately substituted 2-aminomethyl-1,2,3,4-tetrahydroquinoline (seeBritish Pat. No. 1,166,538) is treated with an aldehyde of the formulali -CHO, where R; is defined as aforesaid. This particular reaction isnormally carried out in the presence of a suitable solvent for thealdehyde, e.g., water or ethanol, or it may be carried out in theabsence of a solvent by merely suspending the tetrahydroquinolinecompound in the liquid aldehyde. In general, the reaction is conductedat a temperature that is in the range of from about 0 C. to about C. fora period of about 15 minutes to about four hours.

The N-oxide derivatives of the compounds of this invention, i.e.,N-oxide derivatives of the aforementioned novel substituted hexahydroimidazoquinolines, may be prepared by simply using well-known syntheticmethods to efiect such a conversion from the parent compound, e.g.,oxidation via 30 percent hydrogen peroxide or benzoyl peroxide, etc. Theesters of those compounds containing free hydroxyl groups are alsoprepared by conventional means.

Inasmuch as the substituted hexahydro imidazoquinoline compounds of thisinvention all possess asymmetric carbon atoms at positions 1 and 3a ofthe imidazoquinoline fused ring system, they may exist in separated dandl-optically active forms, as well as in racemic dl-mixtures necessarilyproduced by the present synthetic methods as hereinbefore described. Theinvention contemplates the d, land racemic forms within its scope.

The acids which are used-to prepare the pharmaceuticallyacceptable acidaddition salts of the aforementioned hexahydro imidazoquinoline basecompounds of this invention are those which form non-toxic acid additionsalts, i.e., salts containing pharmacologically acceptable anions, suchas the hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate,phosphate or acid phosphate, acetate, maleate, fumarate, lactate,tartrate, citrate, gluconate, saccharate, methanesulfonate,p-toluenesulfonate and pamoate (i.e., 1,1-methylene-bis-2-hydroxy-3-naphthoate) salts.

The compounds of the invention can be administered alone, but willgenerally be administered in conjunction with a pharmaceutical carrier.The carrier is normally selected with regard to the intended route ofadministration, as well as standard pharmaceutical practice. Forexample, these compounds may be administered orally in the form oftablets containing excipients such as starch or milk sugar (lactose), orin cap sules either alone or on admixture with excipients, or else inthe fonn of elixirs or suspensions containing flavoring or coloringagents, etc. For purposes of parenteral administration, they are bestused in the form of a sterile aqueous solution of a water-soluble salt(e.g., the methanesulfonate salt), which solution may also containsufficient saline or glucose to render the final composition isotonic.

The activity of the compounds of the present invention, asschistosomicides, has been determined by a technique which depends onthe movement of adult sehistosomes from their normal sites in themesenteric veins to the veins within the liver, as effected bychemotherapeutically-active compounds. This technique has been describedin detail in the Journal of Tropical Medicine & Hygiene, Vol 71, pp.139-145 (June, 1968). In the present case, white mice of 3-4 weeks agewere infected percutaneously with 120 cercariae of Schistosoma manroni(East African strain). Eight weeks after infection, the compound to beassessed was administered orally or intraperitoneally at a basic dosageof 25 mg./kg. daily for a period of 4 days, or at 50 mg./kg. in a singledose. Efficacy was then assessed 24 hours after the last dose ofmultiple dosage, or 72 hours after a single dose. Mice were perfusedpost mortem to recover the worms separately from the mesenteric veins,as well as from the hepatic portal vein and from the veins within theliver. The proportional movement of worms from the portal and mesentericveins to the veins within the liver formed the basis for the assessment.

EXAMPLE 1 A suspension of2-isopropy1aminomethyl-6-methyl-7-nitrol,2,3,4-tetra-hydroquinoline (1.5g.) in formalin (10 ml.) was mechanically shaken for a period of twohours, after which time a dark-red solid precipitated. The reactionmixture was then treated with water containing 5N sodium hydroxidesolution (20 ml.) and extracted with diethyl ether (2 X 75 ml.). Theethereal solution was dried over anhydrous magnesium sulfate andevaporated in vacuo to yield a viscous blood-red oil, which crystallizedon standing. The latter material was subsequently dissolved in hotpetroleum ether (b.p. 6080 C.), filtered and allowed to cool to roomtemperature (-25" C.) to yield2-isopropyl-7-methyl-8-nitro-1,2,3,3a,4,5-hexahydroimidazo-[l,5-a]-quinoline (1.25 g.) in the form of red clusters, m.p. 83-84 C.

Anal.

Calcd. for C, H ,N O C, 65.46; H, 7.64; N, 15.27. Found: C, 65.30; H,7.56; N, 14.96.

EXAMPLE 11 A solution of acetaldehyde (2.5 ml.) in absolute ethanol ml.)was added to a solution of 2-isopropylaminomethyl-6-methyl-7-nitro-1,2,3,4-tetrahydroquino1ine 1.0 g.) in absolute ethanol(30 ml.). The slightly exothermic reaction mixture was then allowed tostand at room temperature (25 C.) for 2 hours, after which time thesolution was concentrated in vacuo. The resulting orange oil wasdissolved in hot petroleum ether (b.p. 6080C.) and thereafter allowed tocool to afford 1,7-dimethyl-2isopropyl-8-nitrol,2,3,3a,4,5-hexahydroimidazo-[1,5-a]-quinoline (0.75 g.) as an orangefluffy solid, m.p. l03-l04 C.

Anal.

Calcd. for c,.,H,,N,0,; C, 66.43; H, 7.96; N, 14.53. Found: C, 66.23; H,7.81; N, 14.29.

EXAMPLE I11 Formalin 20 ml.) was added to a solution of6-hydroxymethyl-2-isopropyl-aminomethy-7-nitro-1,2,3,4-tetrahydroquinoline (2.0 g.) in ethanol (125 m1.) and the resultingreaction mixture was set aside at room temperature =25 C.) for a periodof four hours. The solvents were then removed from the solution invacuo, and the crude product obtained in this manner was subsequentlytreated with dilute aqueous sodium hydroxide (5N) and then extractedwith chloroform (2 X 75 ml.). The chloroform solution was dried overanhydrous magnesium sulfate and concentrated in vacuo to afford2-isopropyl-7-hydroxymethyl-8nitro-1,2,3,3a,4,5-hexahydroimidazo-[1,5a]-quinoline, which recrystallized from methanol asa golden yellow fluffy solid (1.85 g.), m.p. l59160 C. Anal.

Calcd. for C H N O C, 61,86; H, 7.22; N, 14.43.

Found: C, 62.00; H, 7.01; N, 14.10.

EXAMPLE 1V Propionaldehyde (5 ml.) was added to a solution of 2-isopropylaminomethyl-6-methyl-7-nitrol ,2,3 ,4- tetrahydroquinoline 1.6g.) in ethanol (50 ml.). After about 15 minutes, an orange solidprecipitated and the reaction mixture was then allowed to stand at roomtemperature (=25 C.) for a further 2 hours. The mixture was thenfiltered, and the orange fluffy solid washed with ethanol and dried invacuo to yield 1.4 g. of l-ethyl-2-isopropyl-7-methyl-8-nitro- 1,2,3,3a,4,5-hexahydroimidazo-[ l,5-a]-quinoline, m.p. l22-124C.

Anal.

Calcd. for C, H ,-,N O C, 67.33; H, 8.25; N, 13.85. Found: C, 67.26; H,8.12; N, 13.75.

EXAMPLE V A large excess of benzaldehyde (7.1 g.) was added to awellstirred solution of 2-iospropylaminomethyl-6-methyl-7-nitro-1,2,3,4-tetrahydroquionoline (1.5 g.) in absolute ethanol (20 ml.) whichwas warmed to about 50 C. via a water-bath. After stirring for a periodof 4 hours, a further quantity of benzaldehyde (10 ml.) was added to themixture and the resulting reaction solution was maintained at this point(i.e., 50 C.) for a further 3 hours. The alcohol was then removed bymeans of evaporation under reduced pressure, and the crude product soobtained was subsequently dissolved in benzene and chromatographed on aneutral alumina column, using benzene as the eluent. The first 25 ml. ofeluent was shown by thin-layer paper chromatographic analysis to containbenzaldehyde and a compound which was not the original startingmaterial. The benzaldehyde was removed (and recovered) by distillationin vacuo (b.p. 65C./ 18 mm. Hg.) and the residue dissolved in hotpetroleum ether (b.p. 60-80 C.). On cooling to room temperature, thesolution soon deposited l-phenyl-2-isopropyl-7-methyl-8-nitro-1,2,3,3a,4,5-hexahydroimidazo-[1,5-a]-quinoline (850 mg.) as orange crystals, m.p. l30l3l C.

Anal.

Calcd. for C ,H N O C, 71.77; H, 7.17; N, 11.96. Found: C, 71.71; H,7.06; N, 12.19.

EXAMPLE VI A mixture of formalin 10 ml.) and 7-chloro-6,8-dimethyl-2-isopropylaminomethyl-1,2,3,4-tetrahydroquinoline 1.05 g.) in ethanol(30 ml.) was shaken for a period of one hour. The reaction mixture wasthen poured into water and the resulting white solid extracted intodiethyl ether. The ethereal solution was dried over anhydrous magnesiumsulfate and subsequently evaporated in vacuo to yield a colorless oil,which was then dissolved in ethyl acetate and treated with a solution ofone equivalent of maleic acid in hot ethyl acetate. Upon the addition ofdry diethyl ether to the combined ethyl acetate solution, there wereultimately obtained 1.2 g. of 2-isopropyl-7,9-dimethyl-8-ch1oro-1,2,3,3a,4,5-hexahydroimidazo-[ l ,5- a]-quinolinehydrogen maleate as a white powder, m.p. 133 C.

Anal.

Calcd. for C,,,l-1 ClN -C H O C, 60.80; H, 6.89; N, 7.09. Found: C,60.83; H, 6.74; N, 6.53.

EXAMPLE VIII Thiophene-Z-aldehyde and 2-isopropylaminomethyl-6-methyl-7-nitro-l,2,3,4-tetrahydroquinoline were reacted in ethanol inthe manner described in Example 11 for acetaldehyde, except that thereaction-time period was extended to 17 hours. The red oil obtained onevaporation of the alcohol was crystallized from petroleum ether (b.p.60-80 C.) and then twice recrystallized from n-hexane to yieldl-(2-thienyl)- 2-isopropyl-7-methyl-8-nitro- 1,2,3,3a,4,5-hexahydroimidazo- [1,5-a]-quinoline as a yellow fluffysolid, mp. 134-l 35 C. Anal.

Calcd. for c,,H,,N,o,s: C, 63.86; H, 6.44; N, 11.76.

Found: C, 63.94; H, 6.59; N, 11.74.

EXAMPLE IX o-Nitrobenzaldehyde was reacted with 2-isopropylaminomethyl-6-methyl-7-nitro 1 ,2,3,4- tetrahydroquinoline inthe same manner as described in Example V for benzaldehyde, except thatthe reaction mixture was refluxed on a steam bath in order to ensurecompleteness. After chromatographing in the usual manner to eliminateimpurities, 1-( 2-nitropheny1)-2-isopropyl-7-methyl-8-nitro- 1,2,3,3a,4,5-hexahydroimidazo-[ 1,5-a]-quinoline was obtained, m.p. 95-97C. Anal.

Calcd. for C M- M0 C, 63.63; H, 6.06; N, 14.14

Found: C, 63.37; H, 6.19; N, 14.32.

EXAMPLE X A solution of 6-ethoxymethy1-2-isopropylaminomethyl-7-nitro-l,2,3,4-tetrahydroquinoline (2.5 g.) in ethanol (90 ml.) wastreated with an alcoholic solution of acetaldehyde (7.5 ml.) in ethanol(30 mL). A mildly exothermic reaction then ensued and after 1 hour,thin-layer paper chromatographic analysis indicated that the reactionwas essentially complete. The reaction solution was then evaporated todryness while under reduced pressure to give1-methyl-2-isopropyl-7-ethoxymethyl-8-nitro-1,2,3,3a,4,'5-hexahydroimidazo-[l,5-a]-quinoline as an orange solid, which was subsequentlyrecrystallized from ethanol to yield 1.6 g. of product, m.p. l03-105C.Anal.

Calcd. for C I-I N O C, 64.85; H, 8.1 l; N, 12.62.

Found: C, 64.45; H, 8.39; N, 12.62

EXAMPLE XI The following substituted hexahydro imidazoquinolinecompounds are prepared by employing the condensation procedure describedin the previous examples, starting from the correspondingZ-aminomethyl-l,2,3,4 tetrahydroquinoline base and the appropriatealdehyde (R -CH0) reagent of choice in each instance:

R1 R2 R3 RI R5 0 N02 H C2H5 CHa CI H n-CuH a H CI H CH3 H N 02 H H H N02 H H H N02 CH3 CH3 n-CaHia N 02 H H H N02 H H CH N02 11-04110 H CflHf,N02 H H III'NO2C6H4 N02 H H p-NOzCuHr N02 H CH3 3-thienyl. N0 H CHZ-thienyl No: II H I1-CuH13 0 N02 11 H CH3 CHQCHQOH CH3 Bl C2H5 HCaH5CH2 n-CuHnOH CHaOH CN n-CoHm H S-iuryl. CHzCHrO CQHIS (I1) CH3 FIl-CaHw ll-CaHn Z-Iuryl. II-CuHizC CH3 CHO Cl H n-CuHm H n-CzsnC0OCH2CHz CH3 Br H H CzHs CH COCCQHHUI)..- CHzOH N02 CH3 H CH5CYOlO-CaHr CH: CN CH3 CH3 H CYQIO-CqHu CHO F H CH3 u-Naphthyl. CQHH2 CH:C] H H fl-Naphthyl CuH (CH2)a CHzOH Bl CzH H CH3 CH3 CH3 N02 H Hll-CqHl: CzH5 CH3 CN 11 II 3431118113 1. ISO-Ca 7 CHQO CO CH F ISO-C3H7H 2-th1enyl. Tart-0 H CHa Cl ll-CaH'; n-CaH- CQI'I5(CH2)3 (CHa)zCHOH CHODr H ISO-CaH7 0-N02CH| CH2CHzOCH3 CH3 NO: ll II ISO-C3H7 CYClO-C4H1...CHQOCzIIr. CH3 II 1l-C H Cycle-0 115.. 3 1" (J11: 011 3-pyrldyl.CHQOCOCiIIH Cl H CH3 2-pyr1dyl. CH Br H II l-pyridyl. H13 CH3 N02 H HC5H5 s CH3 N02 H H 3-thienyl. n-CuHu CH3 H H 2-thieny1.

EXAMPLE xn A mixture of 2.0 g. of 2-isopropyl-7-methyl-8-nitro-1,2,3,3a,4,5-hexahydroimidazo-[l,5-a]-quinoline and a three molar excessof 30 percent hydrogen peroxide in 15 ml. of acetone is stirred at roomtemperature ==2S C.) for a period of 3 days. An additional quantity of30 percent hydrogen peroxide (a five molar excess) is then added and thestirring thereafter continued for a further seven hours. At this point,the reaction is substantially complete and the excess hydrogen peroxideis decomposed by the addition of platinum oxide to the spent mixture.Upon filtering and removal of the solvent by concentration in vacuo,there is obtained a viscous oil as the liquid residue. Trituration ofthe latter material with diethyl ether then gives a powdery solid, whichis subsequently collected by means of filtration and recrystallized fromacetone to afford pure2-isopropyl-7-methyl-8-nitrol,2,3,3a,4,5-hexahydroimidazo-[l,5-a]-quinoline N-oxide as a crystalline solid.

In like manner, the other N-oxide compounds of this invention are eachsimilarly formed by merely employing the appropriate substitutedl,2,3,3a,4,5-hexahydroimidazo-[ l ,5-a]- quinoline base as startingmaterial in the above reaction procedure, in place of the particularquinoline base compound used previously.

What is claimed is:

1. A hexahydro imidazoquinoline compound selected from the groupconsisting of substituted l,2,3,3a,4,5hexahydroimidazo-[l,5-a]-quinoline bases of the formula:

and the N-oxide derivatives and pharmaceutically acceptable acidaddition salts thereof, wherein R, is alkyl having from one to sixcarbon atoms; R, is a member selected from the group consisting ofmethyl and hydroxymethyl; R, is a member selected from the groupconsisting of nitro and chlorine; R, is hydrogen; R, is a memberselected from the group consisting of hydrogen and methyl; and R is amember selected from the group consisting of hydrogen, alkyl having fromone to six carbon atoms, phenyl, nitrophenyl and thienyl.

2. A compound as claimed in claim 1 wherein R, is alkyl having from oneto six carbon atoms, R, is methyl, R, is nitro, and R,, R, and R, areeach hydrogen.

3. A compound as claimed in claim 1 wherein R, is alkyl having from oneto six carbon atoms, R, and R, are each methyl, R is chlorine, and R andR are each hydrogen.

4. A compound as claimed in claim 1 wherein R, is alkyl having from oneto six carbon atoms, R, is hydroxymethyl, R, is nitro, and R,, R, and R,are each hydrogen.

5. A compound as claimed in claim 1 wherein R, and R, are each alkylhaving from one to six carbon atoms, R, is methyl, R is nitro, and R andR, are each hydrogen.

6. A compound as claimed in claim 1 wherein R, is alkyl having from oneto six carbon atoms, R, is methyl, R is nitro, R, and R are eachhydrogen, and R,, is phenyl.

8. A compound as claimed in claim 1 wherein R, is alkyl having from oneto six carbon atoms, R, is methyl, R is nitro, R, and R, are eachhydrogen and R is thienyl.

9. The compound as claimed in claim 3 wherein R, is isopropyl and R ismethyl.

10. The compound as in (ilailll 4 wherein R, is isopropyl.

2. A compound as claimed in claim 1 wherein R1 is alkyl having from oneto six carbon atoms, R2 is methyl, R3 is nitro, and R4, R5 and R6 areeach hydrogen.
 3. A compound as Claimed in claim 1 wherein R1 is alkylhaving from one to six carbon atoms, R2 and R5 are each methyl, R3 ischlorine, and R4 and R6 are each hydrogen.
 4. A compound as claimed inclaim 1 wherein R1 is alkyl having from one to six carbon atoms, R2 ishydroxymethyl, R3 is nitro, and R4, R5 and R6 are each hydrogen.
 5. Acompound as claimed in claim 1 wherein R1 and R6 are each alkyl havingfrom one to six carbon atoms, R2 is methyl, R3 is nitro, and R4 and R5are each hydrogen.
 6. A compound as claimed in claim 1 wherein R1 isalkyl having from one to six carbon atoms, R2 is methyl, R3 is nitro, R4and R5 are each hydrogen, and R6 is phenyl.
 7. A compound as claimed inclaim 1 wherein R1 is alkyl having from one to six carbon atoms, R2 ismethyl, R3 is nitro, R4 and R5 are each hydrogen, and R6 is nitrophenyl.8. A compound as claimed in claim 1 wherein R1 is alkyl having from oneto six carbon atoms, R2 is methyl, R3 is nitro, R4 and R5 are eachhydrogen and R6 is thienyl.
 9. The compound as claimed in claim 3wherein R1 is isopropyl and R5 is methyl.
 10. The compound as in claim 4wherein R1 is isopropyl.